Summary Loss of ovarian hormones during menopause coincides with cognitive decline and increased risk of Alzheimer's disease and related dementias. Due to putative health risks associated with prolonged exposure to estrogens, current guidelines recommend limiting hormone therapy to a few years to treat menopausal symptoms. Work from our lab in rodent models of menopause has demonstrated long-lasting benefits of short- term midlife estradiol treatment on hippocampal function and memory through sustained activation of estrogen receptor (ER) α that are likely permanent, persisting long after the estradiol treatment is terminated. These findings correspond with evidence across multiple species, including humans, that elevated levels of brain ERα are associated with enhanced cognitive aging even in the absence of circulating estrogens. Mechanisms by which increased levels of brain ERα enhance cognitive aging in females with a history of previous midlife estradiol treatment is the broad focus of the current research. The overall hypothesis to be tested by the current studies is that a short-term period of midlife estradiol treatment reverses the negative impact of long- term hormone deprivation on hippocampal function by sustaining levels of brain-derived or neuroestrogens well beyond the period of estradiol treatment. Sustained levels of neuroestrogens allows for insulin-like growth factor-1 (IGF-1) mediated activation of the ERK/MAPK signaling pathway to predominate over the PI3K/Akt pathway, which in turns allows for sustained, continued activation of ERα and subsequent regulation of ERα- mediated genes and proteins important for memory. Guided by supporting data, this hypothesis will be tested by three aims. In Aim 1, we will use a transgenic mouse model that allows for Cre-dependent site-specific inactivation of ERK signaling to determine its role in the ability of IGF-1 to activate ERα and ERα-regulated genes and proteins and impact memory. In Aim 2, we will use transgenic mouse models and viral vector delivery of ERα to manipulate ERK and ERα signaling to determine the respective roles of ERK and ERα in the ability of midlife estradiol exposure to impact hippocampal neuroestrogen synthesis long-term. In Aim 3, we will use pharmacological manipulations to determine if the detrimental effects of long-term ovarian hormone deprivation on the hippocampus and cognition can be reversed by altering the balance of IGF-1 mediated signaling from PI3K/Akt to ERK/MAPK. Completion of the proposed aims is expected to have a positive impact on the study of cognitive aging by elucidating mechanisms by which the postmenopausal cognitive aging trajectory can be enhanced, results that have implications for preventing or delaying onset of Alzheimer's disease and related dementias.

Project Narrative As the population of the United States ages, increased incidence of age-associated dementias including Alzheimer's disease will become a major public health issue. Interventions that could delay the onset of cognitive decline would have a major public health impact. These studies will help determine mechanisms by which short-term administration of estrogens near the time of menopause could exert lasting benefits to the cognitive health of women as they age.